Testosterone Turns Birds Into Bad Parents

Female starlings with a testosterone top-up are better defenders of the nest, but skimp on parental care. The finding may offer clues to why females in general do not have as much testosterone as males.

The spotless starlings of the western Mediterranean compete ruthlessly for nesting sites, and can be killed or seriously injured as a result. When Jose Veiga and Vicente Polo at Spain's National Museum of Natural Sciences in Madrid placed testosterone implants in 30 female starlings they found that these birds tended to be better at acquiring and holding onto their nests, but took less care of their young.

High levels of testosterone may work to a female's advantage where competition for nesting sites is fierce, the authors suggest, but reduce reproductive success elsewhere. The research will be published in a forthcoming issue of The American Naturalist.

Publishing in May, 2008 in The American Naturalist
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Blind Mice See the Light

Blind mice have been made to sense light by inserting a protein derived from algae into their eyes. A similar method could one day be used to treat certain forms of blindness in humans, the researchers hope.

The light-sensitive protein, called channelrhodopsin-2 (ChR2), is used by algae to sense light for photosynthesis. Some researchers are interested in using these light-sensitive proteins to replace damaged or missing photoreceptors in animals' eyes. This happens in several human conditions, including the late stages of a relatively common form of blindness: age-related macular degeneration. At present, there are no cures for such patients, though treatments including gene therapy and laser surgery are being tested.

The algae protein has been used by neuroscientists before in the lab, in order to make 'light switches' that turn neurons of interest on and off in lab animals1. But its use as a therapy against blindness is in very early stages.

If the technique can be perfected, it could allow people rendered totally blind by the loss of photoreceptors able to see - albeit in black and white.

Botond Roska of the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland, and his team looked at mice that were entirely missing photoreceptors in their eyes. These photoreceptors usually feed signals about light to the next layer of cells, called bipolar cells, before a signal is relayed on to the brain, providing a visual image.

The researchers used a harmless virus to carry the protein into the mice's bipolar cells. The protein ended up in only about 7% of the cells this way, but that was enough for light signals to be transmitted to the next layer of the retina - the ganglion cells - and eventually the brain, the team determined through studies of brain activity. While untreated mice didn't respond to light at all, treated mice kept in the dark jumped into action when a bright light was turned on, they report in Nature Neuroscience 2.

It’s difficult to gauge exactly how well the mice could see after the treatment. The team tested vision, rather than just light perception, by showing the mice a series of moving stripes and seeing if they could follow them. The treated mice were better than untreated animals, but "you can't ask the mouse", says Roska. Mouse vision isn’t that good in the first place, he adds, which makes it harder to tell.

A previous attempt at conferring sight on blind mice by a team based at Wayne State University School of Medicine, Detroit, showed that the same technique could activate the brain’s visual cortex3. But these mice did not change their behaviour when lights were turned on, as the mice in Roska’s study did.

The reason for the difference, Roska suggests, may be that in the previous study, ChR2 was randomly inserted into many cell types in the retina. There are over 60 types of cell here, some of which are switched on by light, and others that are inhibited by it. Slotting the light-sensitive protein into all of these cells means the opposing effects might cancel each other out, says Roska, or muddle up the output to the brain so much that a signal can't be interpreted.

Nonetheless, says Zhuo-Hua Pan, who led the previous study in Detroit, “many of the results of this paper nicely confirmed our early findings”.

Roska and his colleagues are already setting up a collaboration with clinical groups to develop the technique for people. But even then, it’s likely to be a last-chance treatment, says Roska. If even a tiny bit of vision remains, other treatments will likely be more useful for some time, says Roska. "The method should only be used if there’s absolutely no vision left," he says.

Released April 27, 2008 by the Friedrich Miescher Institute for Biomedical Research
The Friedrich Miescher Institute for Biomedical Research (FMI), based in Basel,
Switzerland, is a world class center for basic research in life sciences. It was founded in
1970 as a joint effort of two Basel-based pharmaceutical companies and is now part of the
Novartis Research Foundation.
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Scientists at Yale Provide Explanation for How Cancer Spreads

Metastasis, the spread of cancer throughout the body, can be explained by the fusion of a cancer cell with a white blood cell in the original tumor, according to Yale School of Medicine researchers, who say that this single event can set the stage for cancer’s migration to other parts of the body.

Their work was Published in the May issue of Nature Reviews Cancer. The studies, spanning 15 years, have revealed that the newly formed hybrid of the cancer cell and white blood cell adapts the white blood cell’s natural ability to migrate around the body, while going through the uncontrolled cell division of the original cancer cell. This causes a metastatic cell to emerge, which like a white blood cell, can migrate through tissue, enter the circulatory system and travel to other organs.

“This is a unifying explanation for metastasis,” said John Pawelek, a researcher in the Department of Dermatology at Yale School of Medicine and at Yale Cancer Center, who conducted the studies with colleague Ashok K. Chakraborty and several other Yale scientists. “Although we know a vast amount about cancer, how a cancer cell becomes metastatic still remains a mystery.”

The fusion theory was first proposed in the early 1900s and has attracted a lot of scientific interest over the years. Pawelek and his colleagues began their research several years ago by fusing white blood cells with tumor cells. These experimental hybrids the researchers observed, were remarkably metastatic and lethal when implanted into mice. In addition, the scientists noted, some of the molecules the hybrids used to metastasize originated from white blood cells, and these molecules were the same as those used by metastatic cells in human cancers. Pawelek and his team then validated previous findings that hybridization occurs naturally in mice, and results in metastatic cancer.

“Viewing the fusion of a cancer cell and a white blood cell as the initiating event for metastasis suggests that metastasis is virtually another disease imposed on the pre-existing cancer cell,” said Pawelek. “We expect this to open new areas for therapy based on the fusion process itself.”

The research team recently began studying cancers from individuals who had received a bone marrow transplant—a new source of white blood cells for the patient. Genes from the transplanted white blood cells were found in the patient tumor cells, indicating that fusion with white blood cells had occurred. But Pawelek said these studies must be greatly expanded before his team can say with certainty that white blood cell fusion accounts for cancer metastasis in humans.

“To date, the fusion theory and the considerable evidence supporting it have largely been overlooked by the cancer research community,” said Pawelek. “The motivation for our article is to encourage other laboratories to join in.”

Publishing in May, 2008 in the journal Nature Reviews Cancer
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TUESDAY - April 29, 2008-----------------------------------------------------News Archive/Return to Today's News Alerts

In Australia, Even Part-Time Work Can Negatively Affect Breastfeeding

Part-time and casual work among new mothers has almost as big a negative impact on breastfeeding rates as returning to work full-time, says a new study led by the University of Melbourne.

While previous studies have shown that women who return to full-time work are far less likely to be breastfeeding at six months, the new Australian study is the first to show dramatically reduced breastfeeding rates in those who return on a part-time or casual basis. The paper, to be published in the May issue of Acta Paediatrica, says a lack of paid maternity leave and low workplace support for breastfeeding are interfering with the establishment of breastfeeding among Australian women.

Lead researcher Amanda Cooklin, from the University of Melbourne’s Key Centre for Women’s Health in Society, and colleagues Susan Donath (Murdoch Children’s Research Institute and University of Melbourne) and Lisa Amir (La Trobe University) analysed the breastfeeding rates among almost 3700 mothers and babies at six months after the birth.

• Mothers who returned to work full-time within three months of birth were twice as likely to have stopped breastfeeding by the time their baby was six months, than those who were not employed

• Mothers who returned to work full time between three and six months of birth were three times as likely to have stopped breastfeeding by the time their baby was six months than non-employed women.

• Women who returned to work on either a part-time or casual basis after three months were almost as likely to have stopped breastfeeding as those who worked full-time.

Ms Cooklin said study results showed that early postnatal employment was a significant risk factor for an early end to breastfeeding in Australian infants. Previous studies in the US had found mothers who worked part-time had similar breastfeeding patterns to those who were not employed. “In Australia however, a reduced working week does not contribute to mothers’ ability to maintain breastfeeding for six months,’’ Ms Cooklin said.

“Part-time employment is almost as much of a risk factor as full-time employment for an early end to breastfeeding.” Ms Cooklin said a lack of privacy, fatigue, inflexible work schedules and unsupportive employers and colleagues prevented many employed women from maintaining breastfeeding. “Given that the provision of workplace support for breastfeeding remains a matter for individual negotiation, it’s not surprising that a return to work spells the end of breastfeeding for many women.”

Ms Cooklin said lack of paid maternity leave was also affecting breastfeeding rates. “Many women return to work sooner than they would like for financial reasons and this interferes with the establishment of breastfeeding,’’ she said.

The World Health Organisation recommends exclusive breastfeeding for the first six months of life. However, only half of Australian infants receive any breast milk by six months and very few of these infants are exclusively breastfed.

Released May, 2008, in Acta Paediatrica
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Daycare Attendance Cuts Childhood Leukemia Risk 30 Percent

Children who attend day care or play groups have about a 30% lower risk of developing the most common type of childhood leukaemia than those who do not, according to a new analysis of studies investigating the link.

The new research, tpresented at the 2nd CHILDREN with LEUKAEMIA Causes and Prevention of Childhood Leukaemia Conference in London, is the first comprehensive analysis of studies investigating the association between social contact and childhood leukaemia.

“Combining the results from these studies together provided us with more confidence that the protective effect is real. Analysing the evidence in this way gives a more reliable answer to the question and a more precise estimate of the magnitude of the effect,” said the study’s leader, Dr. Patricia Buffler, professor of epidemiology at the School of Public Health of the University of California, Berkeley.

While the analysis does not reveal how intense social contact might ward off childhood leukaemia, it bolsters the theory that children exposed to common infections early in life gain protection from the disease. It is known that environments such as day care centres increase the chance of infections spreading. Some proponents of the theory believe that if the immune system is not challenged early in life and does not develop normally it may mount an inappropriate response to infections encountered later in childhood and that this could provoke the development of leukaemia.

Leukaemia is the most common cancer found in children in the industrialised world, affecting about one in 2,000 children. Incidence of the disease has been on the increase for decades. Acute lymphoblastic leukaemia, or ALL, the type of leukaemia the studies focused on, accounts for more than 80% of cases and most often occurs in children aged between 2 and 5 years. Scientists believe that for most types of childhood leukaemia to develop, there first must be a genetic mutation in the womb, followed by a second trigger during childhood that results in 1% of those children developing the disease. Infection – or the timing of infection - is one of the suspected triggers.

Buffler’s analysis included 14 published studies comprising a total of 6,108 children with leukaemia and 13,704 without the disease. Parents were asked about day care and playgroup attendance, as well as other forms of social interaction with other children. The studies varied in the timing, duration and extent of social contact investigated and in the age groups and types of leukaemia studied. Twelve of the studies found some indication of a protective effect of social interaction with other children, while two found no effect. No study found that social contact increased the risk of childhood leukaemia.

“Our analysis concluded that children who attended day care or play groups had about a 30% lower risk of developing leukaemia than those who did not. Combined results for studies of day care attendance specifically before the age of 1 or 2 showed a similarly reduced risk,” Buffler said. The protective effect became even stronger when the researchers omitted from the analysis 5 studies in which the selection of healthy children for the comparison group relied on methods not considered optimal. In that analysis, children exposed to social contact were almost 40% less likely to go on to develop leukaemia than their counterparts.

In a separate report released at the conference on Tuesday by CHILDREN with LEUKAEMIA, scientists reviewed the evidence from studies that have investigated a link between infection and childhood leukaemia. They examined not only the idea that early life infections protect against the disease but also whether vaccination plays a role. In addition, they examined two other related areas of research: the role of infection during pregnancy and whether infection might be a factor influencing childhood leukaemia risk in situations where the population mix changes. However, the report concluded that the evidence regarding whether infection during pregnancy or in situations of unusual patterns of population mixing influences the risk is inconclusive at present and that further research is necessary.

“On the question of whether infection early in life protects against leukaemia, the best evidence comes from studies of indirect measures of infection - which eliminates many of the problems common in trying to study infections directly - as well as from studies on immune system stimulation and on the genetics of immune responses,” said one of the report’s authors, Dr. Adrienne Morgan, staff scientist at CHILDREN with LEUKAEMIA. “Putting our review together with the new analysis on social interaction, we can say pretty confidently that childcare, breastfeeding and vaccination are good things. This gives a steer to the biologists looking for what mechanisms might be at play,” she said.

Presented April 29 - 30, 2008 at the Causes and Prevention of Childhood Leukaemia Conference, London: Children With Leukemia
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Tumors Like Sugar

Researchers at the Duke School of Medicine apparently have solved the riddle of why cancer cells like sugar so much, and it may be a mechanism that could lead to better cancer treatments.

Jonathan Coloff, a graduate student in Assistant Professor Jeffrey Rathmell's laboratory in the Duke Department of Pharmacology and Cancer Biology, has found that the tumor cells use glucose sugar as a way to avoid programmed cell death. They make use of a protein called Akt, which promotes glucose metabolism, which in turn regulates a family of proteins critical for cell survival, the researchers shared during an April 15 presentation at the American Association of Cancer Research Annual Meeting in San Diego.

In normal cells, growth factors regulate metabolism and cell survival. Removing these factors leads to loss of glucose uptake and metabolism and cell death. Cancer cells, however, maintain glucose metabolism and resist cell death, even when deprived of growth factors.

To study how Akt might affect these processes, Coloff and colleagues introduced a cancer-causing form of Akt called myrAkt, into cells that depend on growth factor to survive. The mutant form of Akt allowed cells to maintain glucose usage and survive even when no growth factors were present, allowing them to bypass a normal safeguard used by cells to prevent cancer development.

The death of normal cells after growth factors are removed is partly accomplished by two proteins called Mcl-1 and Puma. But the cancer-causing version of Akt prevents these two proteins from accomplishing their tasks, allowing the cell to survive when it shouldn't.

Once glucose was withdrawn from the environment, however, Akt was no longer able to maintain regulation of the key targeted proteins Mcl-1 and Puma, and the cells died.

"Akt's dependence on glucose to provide an anti-cell-death signal could be a sign of metabolic addiction to glucose in cancer cells, and could give us a new avenue for a metabolic treatment of cancer," said Dr. Rathmell.t.”

Presented April 15, 2008 at the American Association of Cancer Research Annual Meeting
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Gene Therapy Improves Vision in Small Clinical Trial

Six months after the launch of a clinical trial evaluating the safety of gene therapy for a rare but severe form of retinal degeneration, vision has improved in all three patients who received the treatment. Based on those findings, physicians will proceed with additional clinical trials to investigate the treatment for Leber congenital amaurosis (LCA), an inherited disease that causes severe visual impairment at birth and progresses to complete blindness by the time patients reach their thirties or forties.

The study was led by Katherine High, a Howard Hughes Medical Institute investigator and the director of the Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, where the clinical trial took place. The other senior author was Jean Bennett of the University of Pennsylvania. A second paper also published in the New England Journal of Medicine on April 27, 2008, reports similarly encouraging findings from an LCA gene therapy trial conducted in London.

The researchers say their findings suggest that their gene therapy technique - which uses a viral vector to introduce a corrective gene into the eye - might also be used to treat related forms of retinal degeneration.Researchers There has been some success in using gene therapy to treat other diseases, but these treatments have required patients' cells to be removed, genetically manipulated outside the body, and then reintroduced into the patient. “However, what people have always wanted in gene therapy is, essentially, a medicine in a bottle, where you can inject a medicine into the patient and get a response,” High said.

The results of the new trial represent a success with a viral vector carrying a gene directly into a patient's cells to correct a genetic abnormality. Previously, the therapeutic effects of this type of approach have been undermined by patients' immune responses to the virus. High has worked for years to develop gene therapies, and has encountered this frustration. “Our previous in vivo gene therapy, for hemophilia, showed temporary success, but there was an immune response to the virus that abrogated the effect,” she said. “However, this therapy for LCA2 involved introducing the viral vector into the eye, a relatively `immunoprivileged' site like the rest of the central nervous system. What is exciting about this work is that it demonstrates an in vivo gene therapy that seems to work,” she said.

Mutations in twelve different genes have been found to cause different forms of LCA, all of which are untreatable. High and her colleagues targeted LCA2, which is caused by mutations in a gene called RPE65. RPE65 encodes a protein that the eye needs to produce rhodopsin, which helps convert light into an electrical signal. High and her colleagues engineered a virus called adeno-associated virus to carry a corrective gene for RPE65 into the retina. Prior to testing the therapy in patients, they injected the vector behind the retina of RPE65-deficient dogs and found that the animals' vision was restored. More than seven years after a single treatment, these animals have retained their vision.

This initial clinical trial was designed to test the safety of the treatment on humans. The researchers injected the vector into one eye in each of three patients who are 19-26 years old. They performed two kinds of tests of eye function before and after administering the corrective gene. One set a standard vision tests, asking patients to read an eye chart or navigate an obstacle course. The other physiological test measured the reflexive reaction of the pupil to light. “The visual acuity tests showed that all three of the patients reported improved vision,” said High. “Also, in all three cases, the injected eyes were more effective in driving the pupillary response to light. These were very exciting findings,” she said.

The only complication the researchers have observed thus far is that one patient developed a “macular hole,” a small break in the center of the retina, which was probably a result of the surgical procedure. The hole did not affect the patient's vision, High said, since the patient had no vision in the macula. High pointed out that the disease progresses as patients age, so they would like to include younger patients in subsequent trials. “The younger the subject, the better the chance of response,” she said. “Eventually, we would like to treat children as young as possible after they are diagnosed, because that would offer the maximum chance of effectiveness.”

According to Stone, the results suggest that the same therapeutic approach might be used to treat related diseases. “There are a number of heritable retinal diseases that are similar to RPE65-associated LCA in that the structure of the retina is relatively normal and the visual defect results from the loss of function of a single protein,” he said. “Many of these diseases should be amenable to treatment using an approach that is similar to the one taken in this study.”.”

Published April 27, 2008 in the New England Journal of Medicine
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MONDAY - April 28, 2008------------------------------------------------------News Archive/Return to Today's News Alerts

Extreme Nausea/Vomiting Varies In Pregnant Women by Country

Mothers born in India and Sri Lanka are three times more likely to suffer from extreme nausea and vomiting in pregnancy (hyperemesis gravidarum) than ethnic Norwegians. This finding comes from Norwegian Institute of Public Health’s study of 900, 000 first-time pregnancies registered in the Medical Birth Registry of Norway over a forty year period.
Earlier studies reported that 90 percent of pregnant women experience some degree of nausea and vomiting, whereas 0.5 to 2 percent have hyperemesis gravidarum. Due to dehydration, loss of important electrolytes, malnutrition and weight loss, hyperemesis gravidarum could be life-threatening for mother and baby if left untreated. In the USA it is the commonest cause for hospitalisation during early pregnancy. The cause of hyperemesis gravidarum is unknown.

Åse Vikanes, specialist in gynaecology and obstetrics at the institute’s Division of Epidemiology, wanted to explore whether the mothers’ country of birth affected the prevalence of hyperemesis gravidarum. Vikanes is primary author of the paper “Variations in prevalence of hyperemesis gravidarum by country of birth: A study of 900, 074 pregnancies in Norway, 1967-2005.”

Vikanes and her colleagues collected data from the Medical Birth Registry of Norway, which since 1967 has recorded data on all pregnancies and pregnancy complications. 8, 300 cases of hyperemesis gravidarum were recorded out of 900, 000 pregnancies, giving an overall prevalence of 0.89 percent. Data on the mother’s country of birth and education were recorded by Statistics Norway and linked to pregnancy information through the mother’s unique personal identification number. Socio-demographic factors such as marital status, country of birth, education, age and number of foetuses in each pregnancy were also studied.

“This is one of the largest studies carried out on hyperemesis gravidarum. In contrast to earlier studies we tested the quality of the data and therefore have confidence in our findings” says Vikanes.

Mothers born in India and Sri Lanka had the highest prevalence of hyperemesis gravidarum, followed by those born in Africa (excluding North Africa) and Pakistan by 3.2 percent, 3.1 percent and 2.1 percent, respectively. Ethnic Norwegians, North Americans and Western Europeans had the lowest prevalence by 0.9 percent, 0.9 percent and 0.8 percent, respectively. Maternal age between 20-24 years old, being married, carrying a female foetus or more than one foetus were all socio-demographic characteristics associated with a higher prevalence of hyperemesis gravidarum.

“The difference in prevalence of hyperemesis gravidarum related to the mother’s country of birth cannot be explained by differences in socio-demographic characteristics”, says Vikanes. “We have to look for other explanations such as genetic factors, a change of diet or a history of infections. This topic needs further research to identify ways to prevent this life-threatening and distressing condition.”

Published April 24, 2008, in the Scandinavian Journal of Public Health
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Sensory Treatment Has Promising Results for Children with Autism

Parents of children with autism are increasingly turning to sensory integration treatment to help their children deal with the disorder, and they’re seeing good results. In 2007, 71 percent of parents who pursued alternatives to traditional treatment used sensory integration methods, and 91 percent found these methods helpful.

A new study from Temple University researchers, presented this month at the American Occupational Therapy Association’s 2008 conference, found that children with autistic spectrum disorders who underwent sensory integration therapy exhibited fewer autistic mannerisms compared to children who received standard treatments. Such mannerisms, including repetitive hand movements or actions, making noises, jumping or having highly restricted interests, often interfere with paying attention and learning.

The children assigned to the sensory integration intervention group also reached more goals specified by their parents and therapists, said study authors Beth Pfeiffer, Ph.D., OTR/L, BCP, and Moya Kinnealey, Ph.D., OTR/L, from the Occupational Therapy Department in Temple University’s College of Health Professions. The children made progress toward goals in the areas of sensory processing/regulation, social-emotional and functional motor tasks.

Sensory integration is the ability of the brain to properly integrate and adapt to the onslaught of information coming in through the senses. Dysfunction in this area makes it difficult for people with autism to adapt to and function like others in their environment. They may be hypersensitive to sound or touch, or unable to screen out distracting noise or clothing textures. Their response might be impulsive motor acts, making noises or running away.

Pfeiffer and Kinnealey are part of a group of researchers seeking to bring more scientific understanding to occupational therapy using a sensory integration approach. “It’s been heavily documented that children on the autistic spectrum have differences in the way they process sensory information and respond motorically,” Pfeiffer said. “While more families are seeking out the sensory integration approach because of its positive results, more research is needed to scientifically establish its effectiveness.”

Children receiving sensory integration therapy typically participate in sensory-based activities to enable them to better regulate their behavioral responses to sensations and situations that they find disturbing or painful. A child who is oversensitive to light touch may enjoy rolling and playing in a giant foam pillow, after which he might be more able to calmly explore, touch and play with other textures. This in turn makes self-care such as dressing and washing and classroom activities that require touch more manageable.

Interpreting the child’s behavior as intentional and controllable and not recognizing the underlying cause and hypersensitivities is common in educational and home settings, but is an approach that Kinnealey discourages as stressful for the child.

The study took place this past summer at a camp near Allentown, Pa., for children with autism. Participants were between the ages of 6 and 12 years old and diagnosed with autism or Pervasive Developmental Disorder–Not Otherwise Specified (PDD-NOS). One group (17) received traditional fine motor therapy and the other group (20) received sensory integration therapy. Each child received 18 treatment sessions over a period of six weeks.

A statistician randomly assigned the participants to groups; this information was provided to the project coordinator at the site. The primary researchers were blinded to group assignment and served as evaluators before and after the study. Parents were also blinded to the interventions that their children were assigned to and were not on site. However, there was the potential for the verbal children to talk about the activities that they participated in, which may have influenced the blinding for the parents.

For their outcome data, researchers used a series of scales that measure behavior. While both groups showed significant improvements, the children in the sensory integration group showed more progress in specific areas at the end of the study. “This pilot study provided a foundation for how we should design randomized control trials for sensory integration interventions with larger sample sizes,” Pfeiffer said. “Specifically, it identified issues with measurement such as the sensitivity of evaluation tools to measure changes in this population. “Sensory integration treatment is a widely used intervention in occupational therapy. There is a real need for research such as randomized control trials to validate what we are doing with sensory integration in the profession,” she added.

Published April 25, 2008 at the American Occupational Therapy Association 2008 Conference
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Shape Matters, Even in Hearing

A study from Vanderbilt University establishes a direct link between the cochlea’s curvature and the low-frequency hearing limit of more than a dozen different mammals.

“It turns out that it is the curvature of the cochlea, not its size, that is highly correlated to the low-frequency hearing limit,” says Daphne Manoussaki, assistant professor of mathematics at Vanderbilt University, who headed the new study with Richard S. Chadwick, a section chief at the National Institute on Deafness and Other Communication Disorders (one of the National Institutes of Health, or NIH).

Spiral-shaped cochleae are exclusive to mammals. Birds and reptiles generally have plate-like or slightly curved versions of this critical organ, limiting the span of octaves that they can hear. Animals with tightly coiled cochleae tend to have greater hearing ranges, but previous attempts to associate these auditory effects with the physical characteristics of the cochlea have proven unsatisfactory because they did not take a critical acoustic effect into account.

“The idea that the cochlea’s curvature has a significant effect on hearing has been quite controversial for many years,” says Darlene R. Ketten, a senior scientist at Woods Hole Oceanographic Institution and assistant professor at the Harvard Medical School, who participated in the current study. “Curvature was often dismissed or, when examined, the theories were not entirely satisfactory. Now we have a theory that we have confirmed with a number of concrete examples using real ear shapes and hearing abilities.”

Ketten provided Manoussaki and her collaborators with high-resolution CT scans of the cochleae of a number of different species of land and marine mammals. Together with her biophysicist colleagues, Manoussaki analyzed these shapes and found that low- frequency hearing limits of species ranging from mice to cats to cows to whales varied in step with the ratio of the radii of curvatures at their cochlea’s base to that of its apex. This ratio varies from about two to nine: The larger it is the lower the frequencies that the animal can hear.

“What I like about this is that a macroscopic feature of the ear has such a major effect on our hearing,” says Manoussaki. “As colleagues have pointed out, so much research today is done at the genetic and cellular level that you don’t often see cases like this where simple geometry proves to be so important.”

Published April 25, 2008 in the journal Proceedings of the National Academy of Sciences - PNAS
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Fatty Molecules Linked to Pain and Cancer Also Encourage Cell Motion in Early Development

Fat-derived compounds called prostaglandins - commonly linked to pain, inflammation, reproduction and cancer - also help to choreograph intricate cell movements during early embryonic development.

Critical new details about prostaglandins’ developmental role have been uncovered by Vanderbilt researchers using zebrafish. Their findings highlighted how irregularities in the prostaglandin pathway might influence human development and the spread of cancer. The results also may point to new molecular targets for cancer prevention therapies.

Early in development, vertebrate embryos consist of one layer of cells. These simple embryos must go through a complex reorganization called gastrulation to establish the three primitive layers from which all adult tissues develop – the innermost layer (endoderm), which forms the gut and associated digestive organs; the middle layer (mesoderm), which develops into muscle, bone and cardiovascular organs, and the outer layer (ectoderm), which becomes the skin and nervous system.

“The body is a tube in a tube in a shell,” says Lilianna Solnica-Krezel, associate professor of biological sciences at Vanderbilt University. “Before gastrulation, all of these prospective tubes are at the surface of the embryo. Gastrulation puts these different tissue precursors inside the embryo and gives them a proper shape.”

But little is known about the chemical signals that cause cells to move during this process. Previous studies in mice and zebrafish had suggested that prostaglandins were important in development. Mice lacking an enzyme that synthesizes prostaglandin had numerous developmental defects, but the true effects of prostaglandins on the embryo were obscured, most likely by maternal prostaglandin production. Because they develop outside the mother and are transparent, zebrafish embryos provide a unique model in which to examine prostaglandin’s role in development. So Yong Cha, a graduate student in Raymond DuBois’ lab, director of the Vanderbilt-Ingram Cancer Center and first author on the study, established a collaboration with zebrafish researcher Solnica-Krezel to study this process.

When researchers inhibited the production of a specific type of prostaglandin, PGE2, in zebrafish embryos they found that gastrulation was arrested or slowed down significantly. The resulting embryo was also shorter than an untreated embryo. “What is spectacular,” said Solnica-Krezel, “is that if you just put some prostaglandin back in the culture medium, you rescue the phenotype.”

In another set of embryos, the researchers blocked prostaglandin receptors, EP2 and EP4, causing defects similar to those associated with blocking PGE2 synthesis. When the researchers analyzed cell movement, they found that the shapes and trajectories of embryonic cells were normal - they simply move much slower. This suggested that signaling through the EP4 receptor regulates the speed of cell movements during gastrulation.

Sluggish cell movements could have profound implications for development. “Timing (in development) is really important,” DuBois explains. “If you are traveling and have to get to the train station at a particular time, if you are too slow, you are going to miss the train. If you don’t get on that part of the trip, that disturbs the whole agenda. Development synchronizes or orchestrates a myriad of events in the proper sequence (lots of trains),” says Solnica-Krezel, “and sometimes one train wreck can halt the entire process.”

While ‘bad timing’ during development can spell the end for an embryo, finding this pathway could have beneficial effects in cancer. “The pathways important for regulating development are also regulated abnormally in cancer,” says DuBois, who studies prostaglandin signaling in colon cancer. DuBois previously found that adding PGE2, to cultured cancer cells causes them to move much more rapidly. “We’ve been able to show that some genes in this pathway are really important for cancer cells to spread to the liver,” he says.

Scientists have known that people who take aspirin, a drug that inhibits prostaglandin synthesis, have about a 50 percent reduction in their risk of getting colon cancer, DuBois explains. “We’ve been on a quest for the last 10 years to understand why such a simple drug leads to such a significant reduction in cancer risk,” he says. “There are several parts to that puzzle. This (finding) may be one piece.” “If you could use the zebrafish intelligently to screen for these drugs, it might really speed up the drug discovery process and give us some early clues about the effects we may see in humans,” DuBois says.

Published 2006 in the journal Genes and Development
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